35 years in the AIDS trenches

After helping pave the way to HIV treatment, Dr. Larry Corey wants a vaccine — and a cure

June 13, 2016

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By Mary Engel / Fred Hutch News Service

Dr. Larry Corey speaks at an HIV Vaccine Trials Network conference in Cape Town, South Africa, in October 2013.

Photo by Robert Hood / Fred Hutch News Service

The June morning in 1981 started out routinely enough. Coffee in hand, Dr. Larry Corey, then a young University of Washington medical virologist, picked up a copy of the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly report. What he read is as fixed in his memory as a specimen on a glass slide: Five previously healthy men, all of them gay, had fallen ill or died from a lung infection that typically affects only people with severely damaged immune systems.

Not that he or anyone realized what they were seeing at the time. Corey was on the brink of developing the first antiviral treatment for genital herpes, a feat that would seal his reputation as a force in the infectious disease field before he was even 35. He remembers feeling confident that the scientific community would figure out what was causing these mysterious infections and how to stop them.

They were, of course, the first reported cases of what would become known as AIDS. And that single report would shift the course of Corey’s career. Finding a way to treat, prevent and even cure HIV, the virus found to cause the global scourge, would become the focus of his life’s work over the next 35 years.

Now 69 and the past president and director of Fred Hutchinson Cancer Research Center, Corey was right on one level: Within three years, scientists identified HIV as the virus that hijacks and decimates its victims’ immune systems, leaving them vulnerable to infections they might otherwise have fought off. By another dozen years, they had developed lifesaving combination antiviral drugs to hold the virus in check, building on a road map that Corey created for developing antivirals for herpes virus infections.

What he and no one else foresaw was how rapidly the killer virus would spread or what damage it would cause, killing an estimated 25 million people worldwide, a pace that treatment has slowed but not halted. With an estimated 40 million people living with HIV today, Corey and many others see a vaccine as the best hope to get to an AIDS-free generation.

Today the founder and leader of the world’s largest HIV vaccine network, Corey will deliver a plenary talk on the state of HIV vaccine development at next month’s AIDS 2016 conference, the biannual meeting of the International AIDS Society, in Durban, South Africa. In August, he will be the keynote speaker at the third Conference on Cell and Gene Therapy for HIV cure at Fred Hutch about an even more challenging goal: an HIV cure.

The road to research

Growing up in Detroit, Corey and his two older sisters were the children of immigrants from Russia and Poland. Corey was the “Americanized one” who now kicks himself for never learning the Yiddish, Russian, Polish, Ukrainian and Hebrew languages that filled his household. His father was in the schmatte, or rag recycling, business well before recycling became profitable; his mother was a homemaker. He idolized his oldest sister, Sharon, and the husband she married when Corey was 10. That was when Corey decided to go into medicine because his new brother-in-law was training to be an ophthalmologist. His other sister, Roslyn, also married a physician, “so it was logical to want to be like them,” Corey said.

Collecting scholarships and skipping grades, he graduated from the University of Michigan at 20 to enter the university’s fast-tracked, three-year medical program. Along the way, he started dating Amy Glasser, whose father had supervised the field trials of the Salk polio vaccine. Dr. Jonas Salk was a guest at their 1969 wedding.

When he met one of the great vaccine developers in history, Corey was leaning toward a career in cardiology. Then tragedy struck. His beloved brother-in-law, Dr. Thomas Banks, developed Hodgkin lymphoma. Chemotherapy suppressed his immune system, and he died, not of the cancer but of an infection. He was 37, Corey, 26.

“You could say I’ve never recovered from that,” Corey said. “He was like my brother.”

Infectious diseases became his new passion. After a stint as a public health officer investigating epidemic outbreaks at the CDC during the Vietnam War era, he came to the University of Washington in 1975 as a postdoctoral fellow to research viral infections. His mentor, the legendary Dr. King Holmes, nudged him toward sexually transmitted diseases, specifically genital herpes, a lifelong, recurring infection with no cure and, at the time, no treatment.

Corey recalled turning pale at the suggestion.

“Kosher home, grandfather’s a rabbi in the old country … studious … basically a nerd … and then going to work on sexually transmitted diseases,” he wrote for a 1988 lecture on receiving an award for his work in precisely that area. “My mother was telling people I was going to be a cardiologist. What was I doing here!!”

A herpes breakthrough

In 1982, the fear and stigma surrounding herpes landed the virus on the cover of Time magazine as that era’s “scarlet letter,” a foreshadowing of the even greater HIV fear and stigma to come. By then, Corey was working with biochemist Trudy Elion at Burroughs Wellcome (now GlaxoSmithKline) to show that acyclovir, a new type of drug invented by Elion and directed for the first time at an enzyme specific for a virus, could control and suppress a viral infection.

Half the scientists he knew not only doubted that an antiviral would work, they feared it would cause harm, attacking human cells rather than the virus and causing an autoimmune disorder or even cancer.

“I was young enough and bold enough to say, ‘Let’s see what this drug can do,’” he said of a clinical trial of intravenous acyclovir to treat severe infections. "After the third day, it was, ‘Wow, there’s something special going on here.’” Results were so spectacular that it was obvious who was getting the therapy and who the placebo, even though neither researchers nor patients in the double-blinded study knew.

It was a heady time, Corey said, when “everything you touched worked.”

Today, acyclovir and its successors have reduced mortality rates for babies born with herpes from 80 to 10 percent. Corey also studied the daily use of the antiviral to prevent transmission, an approach that would later be used for HIV. These early studies paved the way for antiviral therapies for HIV, as well as for the viral infections hepatitis B and C.

Buoyed by this early success, Corey started looking around at what to do next. By then, it was apparent that there would be no easy solutions to the mystery disease first reported on that June day in 1981.

He began to focus on HIV.

Early HIV research

Corey opened an HIV lab at UW in 1983. As a physician-scientist, he also treated people with HIV. Each year, he would invite some of them to speak to the virology class he taught for first-year medical students. In those still-early days, many people were afraid to even be in the same room with someone with HIV. Corey wanted to make sure that his students didn’t buy into that fear.

“I would break the class up into small groups and they would have some one-on-one with the person about what it was like to have AIDS,” he said. “They would see me shake hands with the person and hug the person. You don’t get the infection that way. And there’s a humanity aspect to this.”

What hit Corey hardest — the real “humanity aspect” — was that each year, he had to recruit new patients. “The patients I brought in to be with the class one year were never around the next year,” he said. “They all died before you could bring them back. Every single one.”

This was not the first time Corey had reached out to the community of people affected by a disease. As a herpes researcher, he worked with the American Sexual Health Association to establish The Helper newsletter in 1979 to give people with herpes unbiased, accurate information about a virus that until then had been treated with either silence or derision. Today, The Helper continues to provide information online.

But his record of reaching out to patients didn’t seem to count once he became head of a network overseeing clinical trials of HIV treatment and thus the public face of the government and scientific response to AIDS. He and other network leaders came under harsh attack by the AIDS activist group ACT UP in protests born of rage, frustration and grief at the number of people dying of HIV.

Corey in his Fred Hutch lab in 2008

Fred Hutch file photo

The ‘Gang of Five’

Funded by the National Institutes of Health, the AIDS Clinical Trials Group, or ACTG, formed in 1987 to test therapies for HIV. Corey’s UW lab was part of the network, and he became the group’s chairman. With no budget for hotel stays, he would catch a red-eye flight in the early morning from Seattle to Washington D.C. to attend meetings at NIH headquarters in Bethesda, Maryland, returning home on the day’s last flight. In 1990 alone, he made the grueling trip 20 times.

So urgent was the need for therapies that study investigators routinely worked seven-day, 100-hour weeks. Their hard work paid off. The ACTG developed and tested combination drug therapies and then protease inhibitors that by 1996 extended the life expectancy of people with HIV from between six and nine months to 20 years. Today, those who have access to and can tolerate the treatment can live a nearly normal lifespan.

“I think it’s the most remarkable achievement in all of medicine,” Corey said “Just look at the number of lives saved, the number of young adults who are living.”

But in the years leading up to that breakthrough, with people in the hardest-hit cities attending multiple funerals a day, nothing seemed fast except death from AIDS. Protestors stormed AIDS conferences and insisted on a voice in research decisions.

ACT UP protestors dubbed Corey and ACTG investigators Drs. Margaret Fischl of the University of Miami, Martin S. Hirsch of Harvard, Thomas Merigan of Stanford and Douglas Richman of the University of California at San Diego the “Gang of Five” and publicly accused them of “ignoring the anger and frustration of people whose lives are at stake.” In a mock trial on the streets of San Francisco, activists tried the five scientists for “their crimes against gay people.”

Dr. Tony Fauci, the director then and now of the National Institute of Allergy and Infectious Diseases, a part of NIH, scolded the activists in the pages of the Advocate newspaper, saying, “It is particularly devastating and unfair when scientists of good faith and enormous talent are singled out and publicly named as scoundrels.”

Fauci later suggested that community members be allowed to attend the ACTG’s meetings. By the end of 1990, each site sought the local community’s involvement when developing studies. Today, community advisory boards are the norm in HIV research and a model for other disease advocates.

Corey remains one of the staunchest advocates of patient and community involvement. But the bitterness of the protests took their toll.

“It was horrible,” he said, closing his eyes at the memory even more than two decades later. “I was working 100 hours a week, I was so driven. I was given the responsibility of running this organization that was visible to the activists. So it was difficult. I learned from it. I grew from it. This is a reason why we now have such strong community outreach programs at the HIV Vaccine Trials Unit and at Fred Hutch.”

Knowing that a pathway to drug development was in place, Corey abruptly switched fields. Jonas Salk may have had an influence after all: He decided to focus on finding a vaccine to prevent HIV.

In 1998, Fauci asked if he would develop and lead a second large network, this one to test HIV vaccines. Corey assembled a team to run the HIV Vaccine Trials Network, or HVTN, which would be based at Fred Hutch. One of the first people he hired was Steve Wakefield, who continues to work with Corey, to do community outreach.

Corey does not believe that he failed to involve the community before. But with the passage of time, he has tried to glean lessons from the earlier criticism, however painful.

“You sometimes have to have the maturity of age to step back and say, ‘Well, OK, you could have handled that better,’” he said. “It’s why I’ve involved community so much better in the HVTN, it’s why I’ve become sort of a better communicator, it’s why I’ve changed the way I do research. It helped me be a better president, director, leader. There is some wisdom that comes out of parts of your life where you get criticized. You learn from your experience.”

Said Wakefield of the man he’s worked with for decades now, “Larry has a deep moral conviction to take care of the world that he’s in with the talents that he has. But he didn’t get any recognition for the sacrifices that he’s made to solve this epidemic. Until he had grandchildren, I never remember him going on vacations. Now part of his drive to find a vaccine is so his grandchildren will never have to live with HIV.”

The search for an HIV vaccine

Corey was recruited to Fred Hutch in 1996 to lead what is now the Vaccine and Infectious Disease Division. Soon he was deep in the work of finding a vaccine for HIV, which mutates so rapidly even within a single person that antibodies can’t keep up with the changes. Promising trials led to deep disappointments.

His early success against herpes helped him weather the setbacks.

“If I’d known how hard it was going to be — if [the setbacks] had come first — maybe I’d feel differently,” he said. “But I’d had a lot of success and accolades, and it was sort of, OK, you can’t walk away. If you’re not willing to undertake a really tough challenge, who is?”

One of the deepest came in 2007 when a major trial had to be halted when it was found that the vaccine neither prevented HIV infection nor reduced the amount of virus in the blood among vaccine recipients who became infected with HIV. In some cases, it could make the recipient more susceptible to the virus. Corey got the news around the time of his son’s wedding, and not even that joyous event could ease his dismay.

But he and the team he’d built pressed on.

“In Julie [McElrath] and Peter [Gilbert] and Jim Kublin, Steve Wakefield — we have just incredible people,” Corey said. “We are working at the cutting edge of science. The technologies and the techniques and the insights we’re providing are spinning off to other fields.”

Dr. Larry Corey, right, introduces Hutch Award winner Raul Ibanez at the Hutch Award Luncheon at Safeco Field in Seattle in January 2014.

Photo by Robert Hood / Fred Hutch News Service

On the brink

An experimental HIV vaccine regimen being tested in a small clinical trial in South Africa has met the benchmarks to expand into a large-scale trial that could lead to the first licensed vaccine against the virus that causes AIDS. That trial is scheduled to begin in November, with results expected in 2020.

Meanwhile, partnering with a sister network, the HIV Prevention Trials Network, the HVTN launched a clinical trial in April of a new approach called antibody mediated prevention, or AMP. If the experimental antibodies being tested in the AMP trial provide protection as hoped, information gleaned from the study could help scientists figure out how to reverse-engineer a vaccine to elicit the antibodies at the concentrations needed. Corey believes that the path to the promised land of a vaccine that is 80 percent to 90 percent effective may well end up combining both approaches.

Before leaving the Fred Hutch presidency, Corey helped found Juno Therapeutics, a biotechnology company focused on novel immunotherapies for cancer using reprogrammed T cells that directly attack the malignancy while avoiding healthy tissue. “On a pound for pound basis, it’s the most potent killer of cancer we as a scientific field have developed,” he said. “The years of work by my close friends Phil Greenberg and Stan Riddell have placed Fred Hutch at the forefront of this story.”

Corey has since dreamed of using this approach to attempt something that is even more remote than a vaccine: a cure for HIV, a topic he will address at the upcoming Conference on Cell and Gene Therapy for HIV Cure.

Mary Engel is a staff writer at Fred Hutchinson Cancer Research Center. Previously, she was a writer covering medicine and health policy for newspapers including the Los Angeles Times, where she wrote the editorials for a series that won a Public Service Pulitzer for health care reporting. She also was a fellow at the year-long MIT Knight Science Journalism program. Reach her at mengel@fredhutch.org or follow her on Twitter, @Engel140.

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